PROJECT SUMMARY Among all racial/ethnic groups, African Americans (AAs) exhibit the highest colorectal cancer (CRC) incidence and mortality, for reasons that remain poorly understood. The gut microbiome is emerging as a significant contributor to host health and disease. How social determinants interacting with individual factors influence the gut microbiome may be key to understanding racial/ethnic variation in CRC. This study will establish if exposure to structural violence increases psychosocial and physical vulnerability (e.g., anxiety/stress), compounded by one's behavior (e.g., diet), which interacts with the gut microbiome in ways that result in CRC health inequality in urban AAs. Structural violence refers to the multiple ways in which social, economic, and political systems expose particular populations to risks and vulnerabilities leading to increased morbidity and mortality. AAs are more likely to live in urban poverty areas that are fraught with structural violence. Chronic exposure to these societal pressures can elicit adverse neuroendocrine and immune responses that alter the gut microbiome. In Aim 1, we will leverage our ongoing trial of 200 urban AA and non- Hispanic white (NHW) adults (R01 CA204808) at high and low risk for CRC to evaluate: exposure to structural violence at the community and individual level; psychosocial and physical health, dietary behavior, neuroendocrine and immune markers, and colonic mucosa inflammation. From stool and mucosa, gut microbial taxonomic structure, abundance of targeted microbes and their functional genes, shotgun metagenomics, and targeted stool microbial metabolites will be determined. We will ascertain: (1) if the distribution of these exposures and microbial markers differ between AAs and NHWs; (2) if the level of exposure to structural violence is associated with the stool and colonic mucosa microbiomes and stool metabolites; and (3) if exposure to structural violence, microbial data, neuroendocrine/immune markers, and individual diet/health are predictive of colonic inflammation and adenoma using advanced computing approaches. In Aim 2, using a mouse model of APC-driven colon polyps, we will mimic under controlled conditions the type of diet and stress from structural violence observed in urban AA communities. Mice will be exposed to one of three diets (low animal protein/low saturated fat, high animal protein/low saturated fat, or high animal protein/high saturated fat), with or without exposure to episodic aggression (mimicking structural violence). Frequency, size, and severity of colon polyps, abundance of targeted gut microbes and their functional genes, neuroendocrine/immune markers, and colonic inflammation will be assessed and correlated to each animal cohort. The success of this research is supported by a multidisciplinary team of scientists with expertise in microbiology, social science, CRC mouse models, gastroenterology, bioinformatics, and nutrition. Because the gut microbiome can be reshaped by diet and other factors, gaining an understanding of the complex interaction of social determinants, behavior, and biology on the gut microbiome has promise to lead to novel strategies to reduce racial disparities in CRC.